DESCRIPTION: The focus of this project is definition of the interaction between the HIV-1 envelope protein, gp120, the CD4 receptor for the virus, and the CCR5 chemokine receptor which is the predominant co-receptor for HIV-1. We hypothesize that this interaction can be disrupted by small molecules (e.g. peptidomimetics) and that such agents will be effective antiviral agents. The interaction of gp120 with CD4 has been extensively characterized, and the first two aims of the current project will characterize the interaction of gp120 with CCR5. Mutations in envelope other than the V3 loop, as well as scanning and random mutants in the V3 loop will be examined for their effects on gp120 interactions with CCR5. Infection, fusion, and binding assays will be used to characterize the CCR5-gp120 interaction. Chimeric chemokine receptors will also be examined to identify domains in CCR5 critical for gp120 interaction. The third aim of this proposal is to target CCR5 expression to murine macrophages, together with human CD4, to determine if these cells can be infected with HIV-1, as a potential animal model for studies of HIV-1 pathogenesis and drug and vaccine development.